Process of making theobromin.



UNITED STATES EMIL F ISCHER, OF

BERLIN, GERMANY, ASSIGNOR TO C. F. BOEHRINGER S'OEHNE, OF WALDHOF, GERMANY.

PROG ESS OF MAKING THEOBROMIN.

SPECIFICATION formingpart of Ia'etters Patent No. 631,705, dated August 22, 1899.

Application filed September "7, 1897. Serial No. 650,825. (Specimens) To all whom it may concern.-

Be it known that I, EMIL FISCHER, a citizen of Germany, residing at Berlin, Germany, have invented certain new and useful, Improvements in the Preparation of 'lheobromin; and I do hereby declare the following to be a full, clear, and exact description of the invention, such as will enable others skilled in the art to which it appertains to make and use the same.

The present invention relates to the art of preparing the derivatives of Xanthin, and more particularly the alkyl derivatives of the same, such as theobromin.

Theobromin has been demonstrated to be dimethyl-xanthin by myself as the result of exhaustive investigations. (Liebigs Amm- Zen, 215, page 319.) Recent investigations show that its structural formula must be:

I-lN-OO 0O (Jl lCH CII OH .NC-N It was also shown that this body could be artificially obtained by inethylating the lead salt of xanthin with methyl-iodid. (Ibt'cL, page 311.) However, it has not been found possible hitherto to obtain theobromin from the corresponding dimethyl-uric acid. Before explaining the reason for this I will state that the nomenclature adopted in this specification is that proposed by me in Be-m'chte (ler Deuischen Ohem L'schen GeseZZsc7zafl,Vol. 30, No. 5, page 557, and also reported in Site'- ltflgSbEiiChlE (Zer K'dntgl Preu ssischen Akademic, January 8, 1897. According to this nomenclature the nitrogen and carbon atoms in the pnrin, uric acid, or xanthin molecule are nu m hered as follows:

Bearing this in mind, the designations for the compounds hereinafter employed will be perfectly clear and the groupings of the atoms and radicals in the molecule will be apparent.

According to this nomenclature theobromin is a 3-7-dimethyl-xanthin. Now the reason why the corresponding dimethyl-uric acidthe 3-7-dimethyl-uric acid-could not be converted into 3-7 -dimethyl-Xanthin or theobromin is that said 3-7-dimethyl-uric acid was not susceptible of conversion into the corresponding dimethyl-chloro-xanthin if treated with phosphorus-penta-chlorid in the mannet that hydroxycaft'ein or 1-3-dimethyl-uric acid has been converted by the same treat ment, which is set forth in my United States Patent No. 569,489 and also in German Patent No. 86,562. When the 3-7-di1nethyl-uric acid is thus treated, the halogen enters the alloxan nucleus of the uric-acid molecule and 3 7 dimethyl 6 chloro 2 -8 dioxypurin is formed. (See Bem'chte der Deutschen Chem sohen Gesellschaft, 28, page 2486.) At a higher temperature this product will lose a methyl-radical under the influence of phosphorus-penta-chlorid, whereby the same is converted into 7-methyl2-6-8-trichl0ro-purin. (I bid, page 2489.) It is due to this circumstance that all attempts to convert the 3-7-dimethyl-uric acid into the closely-related theobromin have been hitherto fruitless. I have, however, discovered a manner of overcoming this difficulty, and my present invention involves this method devised by me of proceeding from the 3-7-dimethyl-uric acid to 3-7-dimethyl-Xanthin or theobromin.

As shown in my application filed November 13, 1897, Serial No. 658,492, the halogen atom in 3-7-dimethyl-6-chloro-2-8-dioXy-purin may be replaced by an amido radical, thus forming the base 3-7-dimethyl-6-amido-2-8- dioxy-purin it the former3-7-dimethyl-6- chloro-2-S-dioxy-purin-is heated with ammonia. Now I have found that on further treating the resulting amido-derivative with aphosphorus-oxy-halogen compound,such as phosphorus-oxy-chlorid, the same loses the oxygen molecule having the position (8) and is thus converted into 3-7-dimethyl-6-amido- 2-oxy-S-chloropurin, according to the equation:

(A) N QNH,

3 OG ON.CI-I +POCI OII .NONI-I Dimethyl-amido-dioxypurin.

N=QNH Dimethyl-amidooxy-chloropurin.

In the detailed description which is now to follow I will'set forth these three principal steps of my'process under three corresponding heads. In this description the proportions given are all understood to be by weight.

(1 Preparation of3-7-dimeihyZ-6-amido-2- owy-8-chloroptwinfrom 3-7-dimethyZ-6-amido- 2-8-dz'00cypurin.The starting materialthe 3-7-dimethyl-6-amido 2 6 dioxypurin-is a new body, which has been recently discovered and prepared for the first time by me. Its characteristics and mode of preparation have been set forth in an application for Letters Patent of the United States filed by me on November, 13, 1897, and having the Serial No. 658,492. In order to make this specification a full disclosure of my invention, I will first describe the mode of preparing the same and its characteristic properties.

I take seven parts of dimethyl-dioxy-chloropurin, whose mode of preparation and constitution have been described in Berichte dev- Deuschen Ohem-isohen Gesellschafzf, Vol. 28,

page 2486, and whose formulahas by recent investigations been ascertained to be:

0O CN.CH =O N HO,(CH Cl OII .NON.H r and heat them in a digester to 130 centigrade, together with fifty parts of an aqueous solution of ammonia, (satuated at 0 centigrada) and maintain this temperature (130 centigrade) for three hours. On cooling the ammonium salt of the amido compound is separated in copious quantities. The entire mass is evaporated without previous filtering, whereby the ammonia is driven ofi. The residue is lixiviated with cold water. As a result of this lixiviation or washing the new base is obtained as a residue in the form of a grayish-green-colored mass. For the purpose of further purifica-tion this mass is dissolved in hot dilute hydrochloric acid and precipitated with sodium acetate while the solution is hot. The yield is seventy per cent. of the chloro C0111- pound employed. This new base, which forms a crystalline and almost colorless powder, has the formula O I-I N O and the-reaction according to which it is formed is expressed in the following equation:

N=C. O1

This new base is decomposed at a high temperature with a separation of free carbon. It is almost insoluble in hot water,soluble only with difficulty in boiling alcohol, and insoluble in chloroform. It forms permanent salts with mineral acids. The auroehlorate is obtained in the form of fine yellow needles from dilute hot hydrochloric acid. When the salt separates out slowly, it crystallizes in the shape of red laminze or plates. The new base is readily soluble in alkalies. Strong alkalies precipitate the corresponding salt in the form of fine needles. In aqueous ammonia solution the amido compound is readily soluble if kept warm; but it is again precipitated on evaporating ed the ammonia. Dilute nitric acid rapidly destroys the base in the heat, the decomposition being attended by the evolution of gases. After drying the dimethylamido-dioxy-purin, which may be prepared in the manner above described or in any other manner which may be hereafter discovered, at 120 centigrade and finely powdering the same I take one part of the same and add to it ten times its weight of phosphorus-oxychlorid. 1 heat the mixture under pressure- .e. g., in a digester-to 170 centigrade and maintain itat this temperature for four hours,

the mixture being frequently shaken or agitated. A clear solution results, from which, on cooling, a portion of the chloro compound, which is a base, is separated in the form of a hydrochlorate. The mother-liquor after being separated from the precipitate is then evaporated in vacrto in order to drive off the oxy-chlorid. WVater is then added in the proportion of ten parts water to one part of the residue, which is of a tough consistency, while shaking well and cooling in order to prevent a rise in temperature, which would otherwise ensue. The residue is thus gradually brought into solution, forming a darkbrown very acid liquid. I then add an alkali, such as sodadye, in sufficient quantity to neutralize the greater portion of the acid. As a result of this treatment, the hydrochlorate of the new compound, which is a base, is separated or precipitated out in the form of a yellow crystalline mass. After cooling, this mass is then filtered and washed with a small quantity of cold water, (about one part.) The base is then liberated from the'hydrochlorate by dissolving the same and supersaturating the solution with ammonia.

For the complete purification of the new compound it is dissolved in about ninety parts boiling water, a little animal charcoal being added, and the solution is then subjected to crystallization in the well-known manner. The dimethyl-amido-oXy-chloropurin is thus obtained in the form of beautiful long needles, which when air-dried contain three molecules of water of crystallization. The latter escapes at 105 centigrade. This new base has the composition denoted by the formula C H N OOl, or

NzdNH,

o.c o-ncn l ll W cH,.N-cN

The reaction whereby it is formed takes place according to the equation (A) given in the introductory part of this specification.

- The new base has no melting-point, but is decomposed without melting when heated beyond 275 centigrade. It is soluble with difficulty only in cold water and cold alkalies, including ammonia. It is readily recrystallized from hot water and dissolves in appreciable quantities in boiling alcohol. It is very difficultly soluble in chloroform. Of its salts the hydrochlorate, the nitrate, and sulfate are very readily soluble in hot water. On cooling these solutions the salts are obtained in a well-crystalized condition.

From its formula it will be noted that this base and its salts are distinguished by having two methyl radicals linked to the nitrogen atom (3) and (7), respectively, an amido radical linked to the carbon atom (6), an oxygen atom to the carbon atom (2), and a chlorin atom to the carbon atom (8).

(2.) Preparation 0f3-7-dimethyZ-6-ctmtdo-2- oxypztrt-n from 3-7-dimethyZ-G-amido-Q-oxy- 8-ohloropm't'n.l take five parts of the 3-7- dimethyl-6-an1ido 2 oXy- 8 chloropurin described under the first head in a dried and finely-powdered state and pour over the same twenty parts of hydriodic acid of the specific gravity 1.96, and after adding one part of phosphonium iodid I heat the whole on a water-bath and at the same time shake the same. Reduction takes place at once under this treatment. However, no clear solution results; but the mixture is converted into thick crystalline pulp-like mass by virtue of the separation of hydro-iodate of dimethylamido-oxypurin, the said crystalline pulp being darkly colored by free iodin. The warming or heating is then continued and further quantities of phosphonium iodid are added until the reddish-brown color of the crystals and of the mother-liquor is replaced by a pale-yellow color. This change indicates that the reduction is completed. Sufficient water is now added to produce a clear solution when warmed to about 80 centigrade. The said clear solution is then evaporated to dryness on the water-bath. The residue is taken up with a little water (about seven parts at a' temperature of 10 centigrade) and is then supersaturated with cold alkali, such as soda-lye. After cooling the new compound, which is a base, is then liberated from the acid and is separated out slowly in the form of prismatic needles aggregated in the form of star-shaped masses. After allowing the crystals so formed to stand for some time (about three to four hours) they are separated by filtering. The base is then purified by recrystallizing from water. This dimethyl-amido-oxypurin thus crystallized contains three molecules of water of crystallization, which are driven off upon heating to 105 centigrade. The dried base has the formula O H N O or the structural formula N: CLNH 0.0 c-Non, cn

oir,.N-o-N It is formed according to the equation (B) at the beginning of this specification. 3-7-dimethyl-(J-amido-Z-oxypurin dissolves in about two parts of boiling water and in moderate quantities in cold water. In hot alcohol this base is soluble with considerable difficulty. It is soluble with difficulty in chloroform. It forms stable salts which for the most part form pretty crystals. From its formula it will be noted that this base and its salts have the methyl and amido radicals and the oxygen atom bounded to the purin nucleus in the following manner: The methyl radicals are united to the nitrogen atom (3) and (7), respectively. the carbon atom (6), while the oxygen atom is linked to the carbon atom (2).

(3.) Conversion of 3-7-dt'mcth1 Z-6-am'id0-2- owypum'n into 3-7- chmethyZ-2-6-d'i090ypurmor theobr0mim-Fifteen parts of the dimethylamido-oxypurin described above are dissolved in one hundred parts of water and thirty parts of dilute sulfuric acid (twenty-five per cent.) and then heated to 80 centigrade, whereupon 7.5 parts of sodium-nitrite are added in small quantities at a time, the mixture being constantly shaken or agitated and maintained at the above temperature while this addition takes place. This process is completed in about half an hour, and as its result nitrogen escapes and the theobromin or 3-7-dimethyl- 2-6-dioxypurin is separated out in the form of a pale-yellow powder or precipitate. This powder is separated by filtering. The'filtrate is then treated in the same manner as above I with five parts of sodium-nitrite, and thus a further copious quantity of theobromin is separated out. The artificial theobromin thus produced when purified by redissolving in water and recrystallizing from water has all the characteristic properties of natural theobromin or dimethyl-xanthin and is, in fact, identical with the same.

the reaction which results in its production according to my invention is indicated in equation 0 given at the introductory part of this specification.

What I claim, and desire to secure by Let ters Patent of the United States, is

1. As a step in the art of preparing theobro- The amido radical is linked to The main part of' min the process which consists in treating 3-7 dimethyl-6-amido-2-8-dioxypurin with phosphorus-oXy-chlorid.

2. As a step in the art of preparing theobromin the process which consists in heating 3-7- dimethyl-6-amido-2-8-dioxypurin with phosphorus-oxy-chlorid under pressure.

3. As a step in the art of preparing theobromin the process which consists in heating 3-7- dimethyl-6-amido-2-8-dioxy-purin with phosphorus-oxy-chlorid under pressure the mixture being agitated while heated, the proportions being substantially as set forth.

4. As a step in the art of preparing theobromin the process which consists in heating 3-7- dimethyl-6-amido-2 8-dioxypurin with phosphorus-oxy-chlorid under pressure, the mixture being agitated while heated, the proportions being substantially as set forth, then allowing the mixture to cool, then separating the mother liquor from the hydrate of the chloro compound which precipitates from the solution and evaporating the same, in vacuo, then adding water and finally adding an alkali,whereby the remainder of the chloro compound is separated as a hydrochlorate.

5. The process which consists in dissolving the hydrochlorate of 3 7 dimethyl 6 amido- 2-oxy-8-chloropurin and supersaturating the solution with ammonia, whereby the base dimethyl-amido-oXy-chloropurin is liberated.

6. The process which consists in dissolving the hydrochlorate of 3 7 1 dimethyl 6 amido- 2-oXy-8-chloropurin and supersaturating the solution with ammonia, whereby the base dimethyl-amido-oXy-chloropurin is liberated, then separating the liberated base and purifying the same by dissolving it in boiling water and then adding animal charcoal and then crystallizing.

7. As a step in the art of preparing theobromin, the process which consists in treating 3- 7-dimethyl-6-amido-2-oxy-S-chloropurin with a reducing agent.

8. The process which consists in treating 3- 7-dimethyl-6-amido-2-oXy-8-chloropurin with hydriodic acid-and phosphonium-iodid.

9. The process which consists in pouring hydriodic acid over dried and powdered 3-7-dimethyl-6-amido-2-oxy-S-chloropurin and addingphosphonium-iodid and heating the whole gently while agitating, all in the proportions substantially as stated.

10. The process which consists in pouring hydriodic acid over dried and powdered 3-7- dimethyl- 6 amido-2 -oxy- 8-chloropurin and tit adding phosphonium-iodid and heating the whole gently while agitating, all in the proportions substantially as stated, then adding more phosphonium-iodid while the heating is 3-7-dimethyl-6-amido-2-oxy-purin having the formula above given and the following properties: it is soluble in boiling water and moderately cold water and soluble with difficulty in hot alcohol and in chloroform, it crystallizes in the form of prismatic needles, which contain when air-dried three molecules of water of crystallization.

12. The process of preparing theobromin which consists in acting on 3-7-dimethyl-6- amido-2-oxypurin with nitrous acid.

13. The process of preparing theobromin which consists in adding to 3-7-dimethyl-6- amido-2-oxypurin sulfuric acid and a nitrite.

14. The process of preparing theobromin which consists in dissolving 3-7-diinethyl-6- amido-2-0Xypurin in water and sulfuric acid, then heating the solution and adding anitrite.

15. The process of preparing theobromin which consists in dissolving 3-7-dimethyl-6- amido-2-oxypurin in water and sulfuric acid and heating the solution, then adding sodiumnitrite to the solution and agitating, while maintaining the heat, the proportions and temperature being substantially as set forth.

16. The process of preparing theobromin which consists in dissolving 3-7-dimethyl-6- amido-2-oxypurin in water and sulfuric acid and heating the solution, then adding sodiumnitrite to the solution and agitating, while maintaining the heat, the proportions and temperature being substantially as set forth, then draining the precipitated theobromin by filtering, and then treating the filtrate with sodium-nitrite in the same manner as above to obtain an additional yield of theobromin.

17. In the art of preparing theobromin the step which consists in converting 3-7-dimethyl-6-amido- -8-dioxypurin into 3-7-dimethyl-G-amido-2-oxy-S-chloropurin.

18. In the art of preparing theobromin the step which consists in converting 37 -di- 19. In the art of preparing theobromin, the

process which consists in converting 3-7-dimethyl 6 amido 2 oxy 8 chloropurin into 3-7-dimethyl-6-amido-2-oxypurin and then converting the latter compound into theobromin.

20. In the art of preparing theobromin the step which consists in converting 3-7-dimethyl-6-amido-2-8-dioxypurin into 3-7-dimethyl-6 amido 2 oxy -8 chloropurin then converting the latter compound into 3-7-dimethyl-6-amido-2- oxypurin and finally converting the latter compound into theobromin.

21. In the art of preparing theobromin the process which consists in treating 3-7 -dimethyl-6-am id 0-2-8-dioxypurin with phosphorus-oXy-chlorid, then isolating the resulting 3 7- dimethyl G-amido 2 oxy-S chloropurin and treating the same with a reducing agent.

22. In the art of preparing theobromin the process which consists in treating 3-7 -dimeth'yl-6-amido-2-oxy-8-chloropurin with a reducing agent, then isolating the resulting 3-7-dimethyl-6-amido-2-oxypurin and reacting upon the same with nitrous acid.

23. In the art of preparing theobromin the process which consists in treating 3-7 -dimethyl-6-amido-2-8-dioxypurin with ph osphorus-oxy-chlorid, then isolating the resulting 3 7 dimethyl 6 amido 2 oxy- 8 chloropurin and treating the same with a reducing agent, then isolating the resulting 3-7 -dimethy1- 6-amido-2 oxypnrin and acting upon the same with nitrous acid.

In testimony whereof I affix my signature in presence of two witnesses.

EMIL FISCHER. lVitnesses:

LORENZ ACH. FR. AGE 

